Differential activation of signal transducer and activator of transcription (STAT)3 and STAT5 and induction of suppressors of cytokine signalling in Th1 and Th2 cells

Abstract

Cytokines direct the differentiation of naive CD4+ T cells into either IFN-γ-producing Th1 cells or IL-4-producing Th2 cells. In this study, we analyzed the activation of signal transducer and activator of transcription (STAT)1, STAT3 and STAT5 (together with STAT4 and STAT6), and the expression of the recently identified suppressor of cytokine signalling (SOCS) proteins, in differentiated Th1 and Th2 cells, both before and after re-stimulation with anti-CD3 and anti-CD28. In addition to the polarized activation of STAT4 in Th1 cells and STAT6 in Th2 cells, we found that STAT3 and STAT5 are selectively activated in Th1 cells after differentiation. This activation of STAT3 and STAT5 was maintained after TCR re-stimulation. The selective activation of STAT3 and STAT5 in Th1 cells was associated with differential induction of SOCS molecules. After re-stimulation, SOCS1 expression was significantly increased in Th2 cells, but not in Th1 and non-polarized 'Th' cells. Additionally, the level of CIS was higher in Th2 cells compared with Th1 and Th cells. In contrast, the expression of SOCS3 was higher in Th1 cells. The differential induction of SOCS proteins was paralleled by the differential expression of cytokines in re-stimulated Th1 and Th2 cells (IFN-γ and IL-4/IL-13 respectively). Our results suggests that STAT3 and STAT5, possibly regulated by the SOCS proteins, may play a role in the differentiation of Th cells, and in the maintenance of the Th1 and Th2 phenotype.